The overall objective of this program is to study the fibrinolytic system in health and disease. The regulation and control of the fibrinolytic system is related to the plasma level and type of plasminogen, the ability of the system to generate plasminogen activator from plasma components and probably from the vascular endothelial cells, and plasma level of the major plasmin inhibitor, alpha 2-plasmin inhibitor. The molecular biology of the components of the system is being studied and the behavior of the various components in isolated systems is well-established. Studies on physiological activation of the system in the plasma milieu, both in vitro and in vivo, is now being studied, using prototype pure activators, e.g. streptokinase and urokinase. The nature of these activating enzymes is being studied using kinetic methods. The biological half-life, or plasma clearance, of new activator species are being evaluated in animal models for future use as thrombolytic agents in man. New laboratory monitoring methods are being developed for studying the behavior of new thrombolytic agents. A study is being carried out on the identification of variant plasminogens in patients with a history of deep-vein thrombosis and their relationship to the disease.